Global Characterization of Protein Palmitoylation in Trypanosomes Palmitoylation is a posttranslational modification of proteins that can affect how a protein interacts with lipids and proteins in a membrane compartment. Dual aminoacylation with myristate and palmitate is essential for targeting of proteins to lipid rafts, and is a common feature of key molecules in cell signaling. While N- myristoylation is carried out in the endoplasmic reticulum by a single N-myristoyltransferase, S-palmitoylation, and rarely N-palmitoylation (occurring on an N-terminal cys residue), is mediated by one of a number of palmitoyl acyltransferases (PATs), each having its own localization and substrate specificity. S-palmitoylation is essential for the functions of a number of important proteins and is essential in eukaryotes. Thus, the identification and linkage of specific PATs and their substrates constitutes a unique approach to systematic analysis eukaryote biology. In the African trypanosome, Trypanosoma brucei, our LC-MS/MS and RNAi data strongly suggest that protein palmitoylation is an abundant and important modification. In the proposed project, we will conduct a global analysis of protein palmitoylation in T. brucei in a five-year intensive research effort that will determine the palmitoylproteomes of T. brucei, identify the substrate profiles and functions of T. brucei PATs, and investigate this class of enzymes as potential targets for trypanocidal chemotherapy.
Global Characterization of Protein Palmitoylation in Trypanosomes Protein modification by palmitoylation is essential in eukaryotes. In the African trypanosome, Trypanosoma brucei, protein palmitoylation is an abundant and essential modification. We will characterize, in a comprehensive manner, protein palmitoylation in T. brucei, and identify the palmitoylating enzymes that are important for specific cellular processes and protein targeting. Further, we will systematically link each palmitoyl protein with its transferase, which has not been accomplished in any system and will significantly advance the field generally. Because palmitoylation is essential, T. brucei-specific palmitoyl acyltransferases are novel drug targets.
|Sharma, Aabha I; Olson, Cheryl L; Engman, David M (2017) The Lipid Raft Proteome of African Trypanosomes Contains Many Flagellar Proteins. Pathogens 6:|
|Brown, Robert W B; Sharma, Aabha I; Engman, David M (2017) Dynamic protein S-palmitoylation mediates parasite life cycle progression and diverse mechanisms of virulence. Crit Rev Biochem Mol Biol 52:145-162|
|Goldston, Amanda M; Sharma, Aabha I; Paul, Kimberly S et al. (2014) Acylation in trypanosomatids: an essential process and potential drug target. Trends Parasitol 30:350-60|